This invention relates to the use of a nucleoside analogue active against herpes simplex virus (HSV), in the treatment of herpes simplex virus infections, and to pharmaceutical compositions containing the two components.
The disease indication for herpes simplex subtype 1 (HSV-1) is herpes labialis (cold sores), and the disease indication for herpes simplex subtype 2 (HSV-2) is genital herpes.
Herpes Labialis is a common world-wide disease characterized by repeated attacks of versicular eruptions most commonly recognised on the lips and perioral skin. Many patients report pain, swelling and significant cosmetic concerns associated with subsequent ulceration of lesions. Although generally a minor disease, in some patients the consequences of frequent severe attacks can be debilitating. The disease is naturally self-limiting in immunecompetent individuals and recurrent episodes last 7-10 days.
First infection with genital herpes may be severe (primary first episode) if the patient has no previous history of labial or genital herpes infection, while a less severe disease occurs if any antibody response is developed through previous exposure to HSVxe2x80x94non-primary first episode. The most common sequel to primary genital herpes infection is recurrent disease. The attack rate varies greatly but is likely that patients will experience on average 4-5 episodes per year. Symptomatology in these episodes are characterised by painful lesions which progress from papules and vesicles through to ulcers and finally crusts. Lesions may be accompanied by a range of symptoms including pain, tenderness, itching and swelling of the affected area.
EP-A-141927 (Beecham Group p.l.c.) discloses penciclovir, the compound of formula (A): 
and salts, phosphate esters and acyl derivatives thereof, as antiviral agents. The sodium salt hydrate of penciclovir is disclosed in EP-A-216459 (Beecham Group p.l.c.). Penciclovir and its antiviral activity is also disclosed in Abstract P.V11-5 p.193 of xe2x80x98Abstracts of 14th Int. Congress of Microbiologyxe2x80x99, Manchester, England Sep. 7-13, 1986 (Boyd et. al.).
Orally active bioprecursors of the compound of formula (A) are of formula (B): 
and salts and derivatives thereof as defined under formula (A); wherein X is C1-6 alkoxy, NH2 or hydrogen. The compounds of formula (B) wherein X is C1-6 alkoxy or NH2 are disclosed in EP-A-141927 and the compounds of formula (B) wherein X is hydrogen, disclosed in EP-A-182024 (Beecham Group p.l.c.) are preferred prodrugs. A particularly preferred example of a compound of formula (B) is that wherein X is hydrogen and wherein the two OH groups are in the form of the acetyl derivative, described in Example 2 of EP-A-182024, hereinafter referred to as famciclovir.
The compounds of formulae (A) and (B) and salts and derivatives thereof have been described as useful in the treatment of infections caused by herpesviruses, such as herpes simplex type 1 and herpes simplex type 2. All references herein to penciclovir/famciclovir include pharmaceutically acceptable salts, such as the hydrochloride, and solvates, such as hydrates.
When used herein the term xe2x80x98immunosuppressantxe2x80x99 includes pharmaceutical agents such as cytotoxic agents such cyclophosphamide and cyclosporin A and corticosteroids such as hydrocortisone and dexamethasone and non steroidal anti-inflammatory agents.
In one preferred aspect, the immunosuppressant is cyclosporin A.
The anti-herpes simplex virus properties of nucleoside analogues such as penciclovir/famciclovir or ayclovir/valaciclovir are potentially enhanced by administering the compound in conjunction with an immunosuppressant. The rationale is that in mice infected with herpes simplex virus, treatment with an antiviral agent to achieve clearance of the virus is particularly effective when the mice are immunosuppressed with cyclosporin A.